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Fbxl13 regulates centrosome homeostasis and migration through ubiquitin mediated proteolysis

ABSTRACT: F-box proteins are the variable substrate adaptor subunits of the SCF (Skp1, Cul1, F-box) ubiquitin ligases. The family comprise about 69 members with important roles in cancer pathogenesis and cell proliferation. Among the F-box proteins, Fbxl13 is frequently amplified in several cancer patient cohorts suggesting an important role in promoting cancer pathogenesis. However, the main function of Fbxl13 is unknown and its biochemical mechanism of action remains uncharacterised. Here, we show that Fbxl13 specifically interacts with the centrosomal proteins Centrin-2, Centrin-3, Cep152, and Cep192. Fbxl13 is enriched at the centrosome, where it targets Cep192 for ubiquitin mediated proteolysis. In line with this, Fbxl13 overexpression downregulated centrosomal γ-tubulin, and disrupted centrosomal microtubule arrays. Furthermore, depletion of Fbxl13 in U2OS cells corresponds to defects in centrosome duplication and cell motility. Thus, we propose that Fbxl13 is a novel regulator of centrosome duplication and microtubule nucleation activity, highlighting a potential tumourigenic role of Fbxl13 in promoting cell motility.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

SUBMITTER: Philip Charles

LAB HEAD: Benedikt Kessler

PROVIDER: PXD006756 | Pride | 2022-03-02

REPOSITORIES: Pride

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			Action	DRS
	Iso1.mzid.gz	Mzid
	Iso1.pride.mztab.gz	Mztab
	Iso1MLN.mzid.gz	Mzid
	Iso1MLN.pride.mztab.gz	Mztab
	Iso2.mzid.gz	Mzid

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FBXL13 regulates centrosome homeostasis and migration through ubiquitin- mediated proteolysis

Project description:Aberrant centrosome organization with ensuing alterations of microtubule nucleation enables tumor cells to proliferate and invade despite increased genomic instability. CEP192 is a key factors in the initiation process of centrosome duplication and in the control of centrosome microtubule nucleation. However, regulatory means of CEP192 have remained unknown. Here we report that FBXL13, a binding determinant of SCF (SKP1-CUL1-F-Box)-family E3 ubiquitin ligases, is enriched at centrosomes and interacts with the centrosomal proteins Centrin-2, Centrin-3, CEP152, and CEP192. Among these, CEP192 is specifically targeted for proteasomal degredation by FBXL13. Accordingly, induced FBXL13 expression downregulates centrosomal γ-tubulin, and disrupts centrosomal microtubule arrays. In addition, depletion of FBXL13 induces high levels of CEP192 and γ-tubulin at the centrosomes corresponding to defects in cell motility. Together, we characterize FBXL13 as a novel regulator of microtubule nucleation activity and highlight a role in promoting cell motility with potential tumor-promoting implications.

2018-01-16 | PXD008310 | Pride

CEP120 Promotes Centrosome Amplification And Progression Of Gastric Cancer Via USP54-Mediated Deubiquitination Of PLK4

Project description:Centrosomal protein 120 (CEP120) is a 120kD centrosome protein that plays an important role in centrosome replication. Overexpression of CEP120 can lead to centrosome amplification, which is closely associated with tumorigenesis and development. However, there are no reports on the relationship between CEP120 and tumors. In our study, overexpression of CEP120 promoted centrosome amplification in gastric cancer (GC), and the role of CEP120 in promoting GC progression was demonstrated in vitro and in vivo. We demonstrated that CEP120 promotes centrosome amplification and GC progression by promoting the expression and centrosome aggregation of the deubiquitinating enzyme USP54, maintaining the stability of PLK4 and reducing its ubiquitination degradation. In conclusion, the CEP120-USP54-PLK4 axis may play an important role in promoting centrosome amplification and GC progression, thus providing a potential therapeutic target for GC.

2023-01-04 | GSE217567 | GEO

Atypical function of a centrosomal module in WNT signalling drives contextual cancer cell motility

Project description:Centrosomes control cell motility, polarity and migration that are thought to be mediated by their microtubule-organizing capacity. In this study we demonstrate that WNT signalling drives a distinct form of non-directional cell motility that requires a key centrosome module, but not microtubules or centrosomes. Upon exosome mobilization of Planar Cell Polarity proteins, we show that DVL2 orchestrates recruitment of a CEP192-PLK4/AURKB complex to the cell cortex where PLK4/AURKB act redundantly to drive protrusive activity and cell motility. This is mediated by coordination of formin-dependent actin remodelling through displacement of cortically localized DAAM1 for DAAM2. Furthermore, abnormal expression of PLK4, AURKB and DAAM1 is associated with poor outcomes in breast and bladder cancers. Thus, a centrosomal module plays an atypical function in WNT signalling and actin nucleation that is critical for cancer cell motility and is associated with more aggressive cancers. These studies have broad implications in how contextual signalling controls distinct modes of cell migration.

2019-04-26 | GSE129871 | GEO

Oncogene-like induction of cellular invasion from centrosome amplification

Project description:Centrosome amplification has long been recognized as a feature of human tumors, however its role in tumorigenesis remains unclear. Centrosome amplification is poorly tolerated by non-transformed cells, and, in the absence of selection, extra centrosomes are spontaneously lost. Thus, the high frequency of centrosome amplification, particularly in more aggressive tumors, raises the possibility that extra centrosomes could, in some contexts, confer advantageous characteristics that promote tumor progression. Using a three-dimensional model system and other approaches to culture human mammary epithelial cells, we find that centrosome amplification triggers cell invasion. This invasive behavior is similar to that induced by overexpression of the breast cancer oncogene ErbB2 and indeed enhances invasiveness triggered by ErbB2. We show that, through increased centrosomal microtubule nucleation, centrosome amplification increases Rac1 activity, which disrupts normal cell-cell adhesion and promotes invasion. These findings demonstrate that centrosome amplification, a structural alteration of the cytoskeleton, can promote features of malignant transformation. genome-wide human SNP 6.0 arrays from Affymetrix was used to determine the copy number changes of MCF10A cells with extra centrosomes or depleted of MCAK after grown 4 days in 3-D cultures

2014-03-01 | E-GEOD-55042 | biostudies-arrayexpress

Oncogene-like induction of cellular invasion from centrosome amplification

2014-03-01 | GSE55042 | GEO

A centrosomal defect of intestinal stem cells predisposes to Crohn’s Disease [array]

Project description:The intestinal epithelium is a single-cell layer comprising a constellation of specialized cell types that functionally interconnect host physiological systems with extrinsic microbial communities, metabolites, and dietary factors1. Active renewal of the intestinal epithelium relies on stem cells that reside in invaginations of the epithelium known as crypts. Inflammatory Bowel Disease (IBD) disrupts normal functions and/or proportions of cells in the intestinal epithelium, including stem cell programming during epithelial restitution. Genome-wide association studies have provided a powerful means to identify loci and genes contributing to IBD risk and functional annotation of candidate genes have unveiled cellular programs and molecular mechanisms involved in IBD etiology. Here we find that risk for a major form of IBD, Crohn’s disease (CD), is linked to a variant of the Fibroblast Growth Factor Receptor 1 Oncogene Partner (FGFR1OP) locus, which encodes a protein of the centrosome, the microtubule organizing center that generates microtubule structures involved in cell division, polarity, and motility. Deletion of Fgfr1op in mouse intestinal epithelium impaired stem cell division and intestinal crypt architecture causing crypt loss, inflammation and death. Transcriptional, biochemical and morphological analyses demonstrated that Fgfr1op coordinates the centrosome with the actin cytoskeleton and with specialized cell junctions known as desmosomes. We conclude that a genetically inherited centrosomal defect predisposes to CD by affecting renewal of the intestinal epithelium.

2024-06-17 | GSE194311 | GEO

A centrosomal defect of intestinal stem cells predisposes to Crohn’s Disease [scRNA-Seq]

2024-06-17 | GSE194312 | GEO

A centrosomal defect of intestinal stem cells predisposes to Crohn’s Disease [RNA-Seq]

2024-06-17 | GSE195515 | GEO

Molecular Signature of Centrosome Abnormalities in Multiple Myeloma

Project description:A large number of cancer-associated proteins involved in the cell cycle, DNA repair, chaperoning and nucleocytoplasmic transport etc. are involved in the control of centrosome number, duplication, centrosome formation and have been implicated as origin of centrosome abnormalities in cancer. In this study, we performed gene expression profiling with focusing on centrosome-related genes for determining the molecular signature characteristic for centrosome abnormalities in MM patients.

2013-03-21 | E-MTAB-1038 | biostudies-arrayexpress

OFD1 interacts with the Preinitiation complex of translation and regulates translation of specific targets in the kidney

Project description:OFD1 is a centrosomal/basal body protein codified by a transcript that when mutated results in OFD type I (OFDI) syndrome, a pleiotropic disorders associated with ciliary dysfunction. We demonstrate that components of the Preinitiation complex of translation (PIC) colocalize to the centrosome and interact with OFD1. We showed that OFD1 functionally controls the protein synthesis machinery, modulating the translation of specific mRNAs in the kidney. Our results indicate a new role for a centrosomal/basal body protein. The dataset contains the microarray data on total and polysomal RNA from control and Ofd1-IND mutant kidneys at P8.

2017-03-15 | E-MTAB-2827 | biostudies-arrayexpress

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